Contributed by

Biodiversity-related BioenterpriseDevelopment in Brazil

Antonio Paes de Carvalho, MD, PhD, MBA exec

UNIDO Session on Utilization of plants for non-food uses:Challenges and perspectives – March 3, 2010

Atlantic Rain

Forest

Atlantic Rain

Forest

Cerrado & Caatinga

Cerrado & Caatinga

Amazon Forest

(60% in Brazil)

Amazon Forest

(60% in Brazil)

Pantanal(60% in Brazil)

Pantanal(60% in Brazil)

PatagoniaPatagonia

NorthernAndean Biomes

NorthernAndean Biomes

PampasPampasSouthern Andean Biomes

Southern Andean Biomes

22% of the GlobalPlant Biodiversity

>60.000 Species ofVascular Plants

Under 1500 plant species are documented by Brazilian Traditional

Medicine (W.B.Mors et al, 2000). Could modern

bioresearch and biotechnologies add

significantly to potential pharmaceutical value?

BIODIVERSITY-RICH REGIONS IN BRAZIL

ADDING PHARMA VALUETO BIODIVERSTY

REGULATORY BACKGROUNDCBD and National Control over Biodiversity Brazilian Legislation: CGEN/MMA and Special License for CollectionLandholder Informed Consent prior to Access

ASSEMBLING THE SCREENING COLLECTIONExpeditions, Extraction Centers, Dry and Fluid Extract Storage

SCREENINGTarget Selection, Bioassay Development, High Throughput Screening

DEVELOPMENT OF PROVEN BIOACTIVESPhytotherapics and Pure Molecules: funding of Innovation in Brazil

HARNESSING RAW MATERIAL SUPPLY & RETURN OF BENEFITSPlant Identification, selection, multiplication and agro-forestry

TOWARDS THE MARKETMedical Ethics and Regulatory Control by National AgenciesPre-Clinical and Clinical TestingLicensing and Commercialization Contracts: IP Issues

THE EXTRACTA BANK OFCHEMICAL BIODIVERSITY

215 Expeditions covered ~10,000 km2 of Atlantic and Amazonian

Rainforests in Brazil during 1999-2010.

4,905 Plants were collected under rigorous control (GPS, local

Digital Photos, Herbarium Samples). Small extraction samples from plant parts averaged 2.5kg.

11,586 TLC-controlled etanolic extracts yielded 31,492 chemical samples for HTS screening campaigns against targets of interest.

A unified data base controls the Bank and screening results (proprietary software).

ASSEMBLINGTHE SCREENING

COLLECTION

RIO DE JANEIRO & BELÉM:extraction facilities can process up to 15.000 extracts per year

Extractsare storedat – 30°Cuntil use

ASSEMBLINGTHE SCREENING

COLLECTION

•Target choice and Bioassay development•Extract dispensation in 96-well plates

•Plate reorganization after HTS results(“cherry picking”)

TARGETTINGBIOACTIVITY WITH

HTS SCREENING

Medium-High Throughput Screening at EXTRACTA:up to 24,000 operations daily

TARGETTINGBIOACTIVITY WITH

HTS SCREENING

DATA PROCESSING

Target: xxxxAssay: xxxxxRun: Screening 1RI: xxxxxDIPlateID: 1000552 assay plates in duplicateZ' factor: 0.951X2: 8.1RI Ic50: 2.7e-5 M

TARGETTINGBIOACTIVITY WITH

HTS SCREENING

1) Tannin score and removal2) TLC quality control3) Biodirected Extract fractionation in search of active compound• UV-visible spectrometry and HPLC• High definition LC-MS• NMR experiments• X-Ray Crystalography OUTSOURCED

BIODIRECTED CHEMICALFRACTIONATION

EXTRACTA PIPELINE: POSITIVE HITS NEED FINANCING TO RETURN BENEFITS LOCALLY

EXTRACTAINNOVATION PIPELINE

MIC Comparison between 3 selectedextracts and a Commercial Antibiotic against

Meticillin-resistant S. aureus

ANTI-MRSA SELECTEDCRUDE EXTRACTS

ANTI-MRSA EXTRACTS,FRACTIONS AND

PURE COMPOUNDS

Gentam

icin

Tetrac

yclin

eLin

ezoli

deVan

comyc

inCipr

oflox

acin

Erythro

mycin

Clinda

mycin

1037

64F7

F8 F5 F4

0

1

2

3

4

5

6

7

8

MICg/mL

Chl

oram

phen

icol

Cef

tazi

dim

eMIC of Extract 103764 and its purified Fractions

compared to Commercial Antibiotics

Public Herbarium (Goeldi Museum)

CURB – Contract of Usage and Return of Benefits

EXTRACTA (represents Land & IP Holders) Industrial Client

INDUSTRY

R&D Contracts

Academia

Patents

Partnerships in R&D&I

Access Contractswith Promise of Future

Return of Benefits

LandholderConserves and

Grants Access to Biodiversity

Collectors EXTRACTA(Licensed by CGEN)And UFPA

EASTERN AMAZONIANJOINT VENTURE

(ONGOING MODEL)

CLONE BOTANICAL CLASSIFICATION Phytogeographic and biodiversity study

Macro and microanatomical study of “plant drug”

DNA “fingerprinting”

CLONE CHEMISTRY AND BIOACTIVITY TLC, SPE, Column Chromatography & HPLC

Isolation of Bioactive Plant Marker (95% Purity)

Bioactive Compound Structure

CLONAL MULTIPLICATION

Agricultural (cuttings & other)

Micropropagation by Tissue Culture

HARNESSING RAWMATERIAL SUPPLY &

RETURN OF BENEFITS (I)

AGRO-FORESTRY STRATEGY Agro-Forestry Engineering Plan Approval (StateLevel)

Local Aclimatization of Cloned Plantlets at the Farm

Farm Experimental and Producing Clonal Orchards

Underbrush Enrichment with Clones in the Neighborhood of Original Plant Access

CGEN-ASSISTED INDUSTRY-EXTRACTA CURB

The Important Issue of Intelectual Property in PHARMA and the Brazilian Approach to the Solution

Returning Benefits to the Farmer: Engineering of Clonal Planting and Production; Commercialization Goals and Pre-Set Prices; Technology Transfer through Training of Extensionists and Farmhands

Returning Benefits to Associated Institutions and Inventors

HARNESSING RAWMATERIAL SUPPLY &

RETURN OF BENEFITS (II)

www.extracta.com.br

EXTRACTA IS THE RESULTOF THE CONCERTED EFFORT OF MANY…

Alberto C ArrudaAline S Silva

Andrea FC SolbergAngelo C Pinto

Antonio CC CarvalhoAntonio P Carvalho

Benjamin GilbertCeli MH Silva

Cyntia a FreireDaniela Alviano

Daniele F BarrosElisabete Pereira

Ely Simone Gurgel

Fernando L CastroFlavio B Pereira (i.m.)

Gilda MP CarvalhoGraziela L Murad

Guilherme AC PenhaInes Chicarelli (i.m.)Isabella MP Carvalho

Jessica ZarattiniJon Lapham

Jorge L CabralJorge Raimundo

Jorginaldo W OliveiraLuis Carlos P Carvalho

Luzia Trajano

Mara SP ArrudaMA EsquibelMario GomesMilton N Silva

Monica CarvalhoOtavio P MirandaPaulo Annechini

Paulo CG FerreiraRadovan Borojevic

Renata KoverRosana C Lopes

Sergio RWF CostaTauã Bethke